Travatan

Travatan

travoprost

Manufacturer:

Novartis Healthcare

Distributor:

Mundipharma
Full Prescribing Info
Contents
Travoprost.
Description
Each mL of TRAVOPROST (TRAVATAN) 0.004% contains 40 μg travoprost.
Travoprost is a highly selective, potent agonist for the FP prostanoid receptor. Its chemical name is isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3R)-3-hydroxy-4 [(α,α,α-trifluoro-m-tolyl)oxy]-1-butenyl]cyclopentyl]-5 heptenoate. Its molecular formula is C26H35F3O6.
Travoprost is a clear, colorless to pale yellow oil, which is very soluble in acetonitrile, methanol, octanol, and chloroform. It is practically insoluble in water. TRAVOPROST (TRAVATAN) 0.004% Ophthalmic Solution is supplied as a sterile, buffered aqueous solution of travoprost with a pH of approximately 6.0 and an osmolality of approximately 290 mOsmol/kg.
Excipients/Inactive Ingredients: Each mL of solution contains polyquaternium-1, polyoxyethylene hydrogenated castor oil 40, boric acid, mannitol, sodium chloride, propylene glycol, sodium hydroxide and/or hydrochloric acid (to adjust pH); purified water.
Action
Pharmacotherapeutic Group: Ophthalmologicals, anti-glaucoma preparations and miotics-prostaglandin analogues. ATC code: S01E E04.
Pharmacology: Pharmacodynamics: Mechanism of action: Travoprost, a prostaglandin F2a analogue, is a highly selective full agonist which has a high affinity for the prostaglandin FP receptor, and reduces the intraocular pressure by increasing the outflow of aqueous humor via trabecular meshwork and uveoscleral pathways.
Reduction of the intraocular pressure in man starts about 2 hours after administration and maximum effect is reached after 12 hours. Significant lowering of intraocular pressure can be maintained for periods exceeding 24 hours with a single dose.
TRAVOPROST (TRAVATAN) Ophthalmic Solution dosed once-daily in patients with open-angle glaucoma or ocular hypertension produced significant reductions in intraocular pressure (IOP) when used either as primary therapy or adjunctively to Timolol maleate (Timoptic*) ophthalmic solution 0.5% BID.
As primary therapy, TRAVOPROST (TRAVATAN) Ophthalmic Solution, dosed QD, reduced IOP 7 to 9 mmHg. Stable diurnal IOP reductions were achieved as early as 2 weeks after initiation of therapy and were maintained over 6 to 12 month treatment periods in 3 well-controlled studies. The IOP reductions with TRAVOPROST (TRAVATAN) Ophthalmic Solution were superior to those obtained with Timolol maleate (Timoptic*) ophthalmic solution and equal or better than those obtained with Latanoprost (Xalatan*) ophthalmic solution 0.005% QD. TRAVOPROST (TRAVATAN Ophthalmic Solution demonstrated an earlier stabilization of IOP reduction and better IOP control throughout the day compared to Latanoprost (Xalatan*) ophthalmic solution 0.005%. TRAVOPROST (TRAVATAN) Ophthalmic Solution was significantly more effective (up to 1.4 mmHg) than Latanoprost (Xalatan*) ophthalmic solution 0.005% in reducing IOP in black patients.
A responder analysis (IOP reduction ≥ 30% or mean IOP ≤ 17 mmHg) demonstrated that TRAVATAN eye drops had a significantly higher responder rate (56%) compared to Latanoprost (Xalatan*) ophthalmic solution (50%) and which were both significantly greater than Timolol maleate (Timoptic*) ophthalmic solution (40%).
In a 6-month well-controlled study, TRAVOPROST (TRAVATAN) Ophthalmic Solution dosed QD adjunctively to Timolol maleate (Timoptic*) ophthalmic solution 0.5% BID provided additional clinically significant IOP reductions (6 to 7 mmHg).
In a clinical trial, patients with open-angle glaucoma or ocular hypertension who were treated with TRAVATAN eye drops (polyquaternium-preserved) dosed once-daily in the evening demonstrated 8 to 9 mmHg reductions (approximately 33%) in intraocular pressure from 24 to 26 mmHg baseline. Data on adjunctive administration of TRAVOPROST (TRAVATAN) Ophthalmic Solution with timolol 0.5% and limited data with brimonidine 0.2% were collected during clinical trials that showed an additive effect of TRAVOPROST (TRAVATAN) Ophthalmic Solution with these glaucoma medications. No clinical data are available on adjunctive use with other ocular hypotensive medications.
Secondary pharmacology: Travoprost significantly increased optic nerve head blood flow in rabbits following 7 days of topical ocular administration (1.4 micrograms, once-daily). TRAVOPROST (TRAVATAN) Ophthalmic Solution preserved with polyquaternium-1 induced minimal ocular surface toxicity, compared to eye drops preserved with benzalkonium chloride, on cultured human corneal cells and following topical ocular administration in rabbits.
Pharmacokinetics: Absorption: Travoprost is an ester prodrug. It is absorbed through the cornea where the isopropyl ester is hydrolyzed to the active free acid. Studies in rabbits have shown peak concentrations of 20 ng/g of the free acid in aqueous humor one to two hours after topical dosing of TRAVOPROST (TRAVATAN) Ophthalmic Solution. Aqueous humor concentrations declined with a half-life of approximately 1.5 hours.
Distribution: Following topical ocular administration of TRAVOPROST (TRAVATAN) Ophthalmic Solution to healthy volunteers, low systemic exposure to active free acid was demonstrated. Peak active free acid plasma concentrations of 25 pg/mL or less were observed between 10 and 30 minutes post-dose. Thereafter, plasma levels declined rapidly to below the 10 pg/mL assay quantitation limit before 1 hour post administration. Due to the low plasma concentrations and rapid elimination following topical dosing, the elimination half-life of active free acid in man could not be determined.
Biotransformation: Metabolism is the major route of elimination of both travoprost and the active free acid. The systemic metabolic pathways parallel those of endogenous prostaglandin F2a which are characterized by reduction of the 13-14 double bond, oxidation of the 15-hydroxyl and β-oxidative cleavages of the upper side chain.
Elimination: Travoprost free acid and its metabolites are mainly excreted by the kidneys. TRAVOPROST (TRAVATAN) Ophthalmic Solution have been studied in patients with mild to severe hepatic impairment and in patients with mild to severe renal impairment (creatinine clearance as low as 14 mL/min). No dosage adjustment is necessary in these patients.
Toxicology: Preclinical safety data: In ocular toxicity studies in monkeys, administration of travoprost at a dose of 0.45 microgram, twice a day, was shown to induce increased palpebral fissure. Topical ocular administration of travoprost to monkeys at concentrations of up to 0.012% to the right eye, twice daily for one year resulted in no systemic toxicity.
Reproduction toxicity studies have been undertaken in rat, mice and rabbit by systemic route. Findings are related to FP receptor agonist activity in uterus with early embryolethality, post-implantation loss, fetotoxicity. In pregnant rat, systemic administration of travoprost at doses more than 200 times the clinical dose during the period of organogenesis resulted in an increased incidence of malformations. Low levels of radioactivity were measured in amniotic fluid and fetal tissues of pregnant rats administered 3H-travoprost. Reproduction and development studies have demonstrated a potent effect on fetal loss with a high rate observed in rats and mice (180 pg/mL and 30 pg/mL plasma, respectively) at exposures 1.2 to 6 times the clinical exposure (up to 25 pg/mL).
Indications/Uses
Decrease of elevated intraocular pressure in patients with ocular hypertension, open angle glaucoma or chronic angle-closure glaucoma.
Dosage/Direction for Use
Use in adults, including the elderly population: The dose is one drop of TRAVOPROST (TRAVATAN) Ophthalmic Solution in the conjunctival sac of the affected eye(s) once daily. Optimal effect is obtained if the dose is administered in the evening.
Nasolacrimal occlusion or gently closing the eyelid after administration is recommended. This may reduce the systemic absorption of medicinal products administered via the ocular route and result in a decrease in systemic adverse reactions. If more than one topical ophthalmic medicinal product is being used, the medicinal products must be administered at least 5 minutes apart. If a dose is missed, treatment should be continued with the next dose as planned. The dose should not exceed one drop in the affected eye(s) daily. When substituting another ophthalmic antiglaucoma agent with TRAVOPROST (TRAVATAN) Ophthalmic Solution, the other agent should be discontinued and TRAVATAN eye drops should be started the following day.
Paediatric population: The efficacy and safety of TRAVOPROST (TRAVATAN) Ophthalmic Solution in patients below the age of 18 years have not been established and its use is not recommended in these patients until further data become available.
Hepatic and renal impairment: TRAVOPROST (TRAVATAN) Ophthalmic Solution has been studied in patients with mild to severe hepatic impairment and in patients with mild to severe renal impairment (creatinine clearance as low as 14 mL/min). No dosage adjustment is necessary in these patients.
Method of Administration: For ocular use. The patient should remove the protective overwrap immediately prior to initial use. To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip of the bottle.
Overdosage
No cases of overdose have been reported. A topical overdose is not likely to occur or to be associated with toxicity. A topical overdose of TRAVOPROST (TRAVATAN) Ophthalmic Solution may be flushed from the eye(s) with lukewarm water. Treatment of an accidental ingestion is symptomatic and supportive.
Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Special Precautions
TRAVOPROST (TRAVATAN) Ophthalmic Solution may gradually change the eye color by increasing the number of melanosomes (pigment granules) in melanocytes. Before treatment is instituted, patients must be informed of the possibility of a permanent change in eye color. The change in iris color occurs slowly and may not be noticeable for months to years. Unilateral treatment can result in permanent heterochromia. The long term effects on the melanocytes and any consequences thereof are currently unknown. The change in eye color has predominantly been seen in patients with mixed colored irides, i.e., blue-brown, grey-brown, yellow-brown and green-brown; however, it has also been observed in patients with brown eyes. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery in affected eyes, but the entire iris or parts of it may be become more brownish. After discontinuation of therapy, no further increase in brown iris pigment has been observed.
In controlled clinical trials, periorbital and/or eyelid skin darkening has been reported in association with the use of TRAVOPROST (TRAVATAN) Ophthalmic Solution. TRAVOPROST (TRAVATAN) Ophthalmic Solution may gradually change eyelashes in the treated eye(s); these changes include increased length, thickness, pigmentation, and/or number of lashes. The mechanism of eyelash changes and their long term consequences are currently unknown.
TRAVOPROST (TRAVATAN) Ophthalmic Solution have been shown to cause slight enlargement of the palpebral fissure in studies in the monkey. However, this effect was not observed during the clinical trials and is considered to be species specific.
There is no experience of TRAVOPROST (TRAVATAN) Ophthalmic Solution in inflammatory ocular conditions; nor in neovascular, angle-closure, narrow-angle or congenital glaucoma and only limited experience in thyroid eye disease, in open-angle glaucoma of pseudophakic patients and in pigmentary or pseudoexfoliative glaucoma. Macular edema has been reported during treatment with prostaglandin F2a analogues. Use TRAVOPROST (TRAVATAN) Ophthalmic Solution with caution in aphakic patients, pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for macular edema.
Skin contact with TRAVOPROST (TRAVATAN) Ophthalmic Solution must be avoided as transdermal absorption of travoprost has been demonstrated in rabbits. TRAVOPROST (TRAVATAN) Ophthalmic Solution contain propylene glycol which may cause skin irritation. TRAVOPROST (TRAVATAN) Ophthalmic Solution contain polyoxyethylene hydrogenated castor oil 40 which may cause skin reactions in patients with known predisposing risk factors for iritis/uveitis, TRAVOPROST (TRAVATAN) Ophthalmic Solution should be used in caution with patients with active intraocular inflammation Periorbital and lid changes including deepening of the eyelid sulcus have been observed with prostaglandin analogues.
Prostaglandins and prostaglandin analogues are biologically active materials that may be absorbed through the skin. Women who are pregnant or attempting to become pregnant should exercise appropriate precautions to avoid direct exposure to the contents of the bottle.
Contact lenses: TRAVOPROST (TRAVATAN) Ophthalmic Solution contains benzalkonium chloride which may cause irritation and is known to discolor soft contact lenses. Avoid contact with soft contact lenses. Patients must be instructed to remove contact lenses prior to application of TRAVOPROST (TRAVATAN) Ophthalmic Solution and wait at least 15 minutes before reinsertion. [Only for products containing benzalkonium chloride].
Effects on the ability to drive and use machines: As with any eye drop, temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs at instillation, the patient must wait until the vision clears before driving or using machinery.
Use In Pregnancy & Lactation
Women of childbearing potential/contraception: TRAVOPROST (TRAVATAN) Ophthalmic Solution must not be used in women of child bearing age/potential unless adequate contraceptive measures are in place.
Fertility: There are no data on the effects of TRAVOPROST (TRAVATAN) Ophthalmic Solution on human fertility. Animal studies showed no effect of travoprost on fertility at doses more than 250 times the maximum human ocular dose.
Use in Pregnancy: Travoprost has harmful pharmacological effects on pregnancy and/or the fetus/new-born child. TRAVOPROST (TRAVATAN) Ophthalmic Solution should not be used during pregnancy unless clearly necessary. There are no limited amount of data from the use of [Travoprost Eye Drops, Solution] in pregnant women. Studies in animals with travoprost have shown reproductive toxicity.
Use in Lactation: It is unknown whether travoprost/metabolites are excreted in human milk. The use of TRAVOPROST (TRAVATAN) Ophthalmic Solution by breast-feeding mothers is not recommended.
Adverse Reactions
TRAVOPROST (TRAVATAN) Ophthalmic Solution (benzalkonium chloride preserved) was administered once daily as monotherapy or adjunctive therapy to timolol 0.5%. No serious ophthalmic or systemic undesirable effects related to the product were reported in any of the clinical studies. The most frequently reported treatment-related undesirable effect with TRAVOPROST (TRAVATAN) Ophthalmic Solution (benzalkonium chloride preserved) monotherapy was hyperaemia of the eye (22.0%), which included ocular, conjunctival, or scleral hyperaemia. Hyperaemia was mild in 83.6% of those patients who experienced it. Almost all patients (98%) who experienced hyperaemia did not discontinue therapy as a result of this event. In phase III clinical studies ranging from 6 to 12 months in duration, hyperaemia decreased over time. In a post approval long-term clinical study of 5 years duration involving 502 patients, TRAVOPROST (TRAVATAN) Ophthalmic Solution were administered once daily. No serious ophthalmic or systemic undesirable effects related to TRAVOPROST (TRAVATAN) Ophthalmic Solution were reported in the clinical study. The most frequently reported treatment-related undesirable effect with TRAVATAN eye drops was iris hyperpigmentation (29.5%). Hyperaemia of the eye assessed as related to the use of TRAVOPROST (TRAVATAN) Ophthalmic Solution was reported at an incidence of 10.0% with 2% of patients reporting hyperemia of the eye discontinuing study participation due to the undesirable effect.
In 2 clinical trials involved in the development of TRAVOPROST (TRAVATAN) Ophthalmic Solution (polyquaternium-preserved), 201 patients were exposed for up to 3 months. No serious ophthalmic or systemic undesirable effects related to the product were reported in either of the clinical trials. The most frequently reported treatment-related undesirable effect with TRAVOPROST (TRAVATAN) Ophthalmic Solution (polyquaternium-preserved) was hyperaemia of the eye (18.9%), which included ocular or conjunctival hyperaemia. One patient (0.5%) discontinued study participation due to hyperemia of the eye.
The following adverse reactions have been reported during clinical studies with TRAVOPROST (TRAVATAN) Ophthalmic Solution and are classified according to the subsequent convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). Within each frequency-grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 1.)

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Additional adverse reactions identified from post-marketing surveillance include the following. Frequencies cannot be estimated from the available data. Within each System Organ Class adverse reactions are presented in order of decreasing seriousness. (See Table 2.)

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The following adverse reactions have been reported during a clinical study with Travoprost 30 micrograms/mL eye drops, solution and are classified according to the subsequent convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). Within each frequency-grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 3.)

Click on icon to see table/diagram/image
Drug Interactions
No clinically relevant interactions have been described.
Caution For Usage
Incompatibilities: None known.
Specific in vitro interaction studies were performed with TRAVATAN eye drops and medicinal products containing thiomersal. No evidence of precipitation was observed.
Storage
Store at temperatures not exceeding 30°C.
Discard 4 weeks after opening.
ATC Classification
S01EE04 - travoprost ; Belongs to the class of prostaglandin analogues. Used in the treatment of glaucoma.
Presentation/Packing
Ophth soln 0.004% (clear, colorless solution) x 2.5 mL
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